Autism is characterized by core social impairments which limit patients' ability to form and maintain meaningful social relationships. At present, antipsychotic medications are the only pharmacotherapeutic option approved to treat autism. However, these agents mainly target associated symptoms (e.g., irritability), have unfavorable side-effects (e.g., lethargy, weight gain), and remain ineffective in treating the social features f this disorder. Developing new medications that specifically target social functioning thus will address a critical unmet need. A large body of research has shown that the closely related neuropeptides arginine-vasopressin (AVP) and oxytocin (OT) play critical roles in adaptive social functioning. For instance, AVP or OT impairments induced pharmacologically or transgenically produce a variety of social deficits in animals. Importantly, single-doses of intranasally administered OT improve several complex social functions (e.g., processing of social information, emotion recognition) in people with autism. Although intranasally administered AVP improves social cognition and memory in neurotypical individuals, and has been used safely for years to treat diabetes insipidus and nocturnal enuresis, no studies have tested the effects of AVP treatment on social functioning in individuals with autism. However, preclinical research has shown that in an OT receptor null (Oxtr-/-)mouse model of autism, social behavior is modulated selectively through brain AVP V1a receptors and that AVP administration rescues social deficits in these animals. Moreover, in other preclinical models, AVP, acting via V1a receptors, more selectively enhances male social behavior than does OT. In contrast, OT, acting via OT receptors, more selectively enhances female social behavior. Given that autism is a predominantly male-biased disorder, that in animals AVP is more important than OT for male social behavior, and that even so, acute OT does help male autistic patients, we hypothesize that AVP will be particularly effective in treating social symptoms in autism. The first step is to test whether AVP ameliorates social impairments in autism and whether males respond more robustly to AVP than females. We will test the effects of single-dose (20 IU) and 4-week (20 IU BID) intranasal AVP administration on social deficits in 50 high functioning males and females with autism aged 6 to 12 years using a double-blind, randomized, placebo controlled, parallel design. Study outcome measures are improvements on parent ratings of the Social Responsiveness Scale (SRS) and laboratory-based assessments of social behavior and cognition (i.e., facial emotion recognition, eye gaze to social cues, social memory, and social perceptual abilities). Consistent with preclinical evidence, we predict that AVP will improve social functioning in individuals with autism. Data from this study will be leveraged to secure additional funding to initiate head-to-head comparisons of AVP and OT treatment in a larger autism cohort. This research has high potential to lead to the development of the first effective treatments and earlier interventions for social impairments in individuals wth autism.